Abstract
An intrinsic link between metabolism and function in immune cells, and in particular macrophages, has been well established recently. However, the molecular mechanisms controlling the metabolic switch in these sentinel cells for their integral roles in host defense, inflammation, homeostasis, and pathogenesis remain largely unknown. Here, we identify the master transcription factor NF-κB RelA as a vital cell-intrinsic checkpoint restricting aerobic glycolysis to favor mitochondrial oxidative phosphorylation (OXPHOS) and "M2" activation (alternative anti-inflammatory and pro-tumorigenic activation, in contrast to classical pro-inflammatory and anti-tumor M1 activation) of macrophages under oncogenic stress. RelA specific knockdown or genetic deletion in macrophages causes metabolism to shift away from OXPHOS toward glycolysis, resulting in drastically decreased oxygen consumption but significantly increased lactate and ATP production. The metabolic change in RelA deficient cells is associated with the decrease in the expressions of the OXPHOS gene SCO2 as well as the M2 marker and function genes arginase-1 and VEGF. These data suggest that RelA induces SCO2 expression to enhance OXPHOS and restrict glycolysis in macrophages for their pro-tumorigenic activation.